October 22, 2013

With nearly 200 million infected people worldwide, hepatitis C virus (HCV) represents a significant public health issue. One of the most important challenges is that although the immune system seems to be responsible for much of the disease-associated morbidity, including liver cirrhosis, it is also successful at clearing viral infection for a significant number of patients.

In his European Research Council (ERC)-funded project entitled HCV_IMMUNOLOGY ('The paradoxical role of type I interferons in hepatitis C disease pathogenesis and treatment'), Dr Albert and his team are attempting to elucidate the complex interplay between HCV and the host's immune response from the perspective of type I interferons (IFNs) and IFN-induced gene products.

The project is aimed primarily at developing more effective treatments. Indeed, the team has already formulated a better approach to predicting whether patients will respond to a particular therapy.

Prior to HCV_IMMUNOLOGY, Dr Albert had spent several years working at the French National Institute of Health and Medical Research, developing partnerships with clinicians and epidemiologists in France, Egypt and the United States. This gave him a clearer insight into the way the disease develops and the immune response responds in both acute and chronic HCV infection.

IFNs are proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites or tumour cells. They allow communication between cells and trigger the immune system's protective defences.

HCV_IMMUNOLOGY research is divided into three strands. First, the role of endogenously produced IFNs in the clearance of HCV during acute infection is examined in patient samples. The paradoxical role these endogenous IFNs play in making chronically infected patients resistant to exogenous IFN therapy is being investigated.

Secondly, Dr Albert is working to characterise the effect of IFN and IFN-induced gene products on the indirect activation of HCV-reactive CD8+ T cells by a mechanism called cross-priming.

Finally, mouse models are being used determine the in vivo pro- and counter-inflammatory effects of IFN and IFN-induced gene products and disease pathogenesis.

Dr Albert believes his team's work will contribute to a deeper understanding of HCV disease pathogenesis, and lead to the development of new diagnostic tools and better therapeutic strategies.

The team has already discovered biomarkers predictive of viral clearance. This could help clinicians to identify, before treatment, which individuals will respond to IFN-based therapy.

Dr Albert received a European Research Council (ERC) Starting grant of around EUR 1.1 million. The project ends in June 2014.

It's not time yet for biopharmaceutical juggernaut Gilead Sciences (NASDAQ: GILD ) to report earnings -- that will come next week. But this is, nonetheless, the most important week of the year for the company.

On Wednesday, the Food and Drug Administration is set to release its briefing documents on Gilead's oral hepatitis C drug sofosbuvir, ahead of a Food and Drug Administration advisory panel meeting Friday. This, without question, is a meeting that could make or break Gilead for the remainder of the year.

Why the buzz?Right now you're probably wondering what the big deal is given that biopharmaceutical companies have FDA panel meetings all the time. The reason sofosbuvir is so important is that it treats the chronic form of Hepatitis C, which afflicts some 3.2 million people in the United States (many unknowingly) and may lead to cirrhosis of the liver or even liver cancer over the long run. The overall market potential in hepatitis C treatments could be as high as $20 billion, which is more than enough to make most pharmaceutical companies get wide-eyed.

What has hep-C patients so excited -- and what makes sofosbuvir so revolutionary -- is that an FDA approval of the oral drug would mean that some patients would no longer be required to take the drug with IV interferon. The problem with interferon-based therapies is that they can give patients flu-like symptoms for the duration of a treatment course that can last up to 48 weeks.

What sofosbuvir could potentially replaceWe've come an incredibly long way in a short amount of time in treating hepatitis C. In 2011, we saw two new oral drugs approved that were to be used in combination with intravenous interferon: Vertex Pharmaceuticals' (NASDAQ: VRTX ) Incivek and Merck's (NYSE: MRK ) Victrelis.

Prior to Incivek and Victrelis, the standard of treatment for hep-C patients was a combination of peginterferon and ribavirin, which demonstrated a response (not effectiveness... just a response) in fewer than 50% of patients. When Incivek rolled around with a late-stage sustained virologic response, or SVR, after 24 weeks of 79%, investors and patients' eyes were opened in a big way. Over the months following its launch, Incivek would become the quickest drug ever to reach $1 billion in sales. The good times, though, wouldn't last long thanks to the development of Gilead's sofosbuvir and AbbVie's (NYSE: ABBV ) direct-acting antiviral combo drug.

Is sofosbuvir really that good?You're probably wondering what makes sofosbuvir so special. The investing community got its first taste of the treatment's potential in a midstage trial in which it delivered an SVR (i.e., no detectable levels of the hepatitis C virus) after just 12 weeks in 100% of all 25 patients. Keep in mind here that Incivek's 79% SVR was after 24 weeks. While Gilead's sofosbuvir wouldn't continue its perfect ways in late-stage studies, it would certainly give shareholders all the more reason to believe in its blockbuster potential.

Gilead ran four late-stage safety and efficacy trials using sofosbuvir on six different hep-C genotypes. The most encompassing was its Neutrino trial, which consisted of patients with genotypes 1, 4, 5, and 6. Genotype 1 is by far the most common and the one that biopharmaceutical companies are most geared toward treating. The results of Gilead's 327-patient trial showed that peginterferon plus ribavirin with oral sofosbuvir delivered 12-week SVR of 90% in treatment-naive patients. The results were just as encouraging for genotype 2 and 3 patients: its Positron trial delivered an SVR of 78% after just 12 weeks in patients who were intolerant of interferon.

So yeah -- it's really that good!

Is it a slam dunk for approval?I believe my Foolish colleague Brian Orelli said it best yesterday, "The FDA's job is to find every potential issue, no matter how small." I wholeheartedly agree with Brian that there doesn't appear to be anything inherent in the data that would suggest sofosbuvir isn't ripe for approval on an efficacy basis. On paper, it looks superior to both Incivek and Victrelis across all of the major hepatitis C genotypes.

Where the product could get tripped up is in either the manufacturing aspects or perhaps the long-term safety aspects of taking sofosbuvir. Don't misconstrue what I'm saying here -- there hasn't been anything to this point to suggest there is a safety problem with sofosbuvir. I'm merely reiterating what Brian noted -- that there's a strong possibility that the FDA will find something to point out. Therefore, I'd call it as close to a slam dunk on efficacy as you can get prior to an FDA panel meeting, but there are always going to be question marks surrounding long-term usage safety and manufacturing procedures heading into advisory meetings like this.

If approved, will sofosbuvir have a cakewalk to blockbuster success?Now here's the tricky part: A positive opinion by the FDA's panel, and even an eventual FDA approval, won't completely put Gilead at the head of the pack. But it'll certainly place it near the top.

FDA approval of sofosbuvir would likely push Incivek and Victrelis out of the picture. But Gilead will still need to contend with AbbVie's very successful direct-acting antiviral combo, which has earned the highly coveted breakthrough therapy designation and delivered an equally impressive SVR of 97% on 79 patients after 12 weeks in a midstage study. AbbVie is conducting late-stage studies on its DAA combo drug and should deliver top-line data soon.

There are other competing pipeline products waiting in the wings, but few are going to be able to keep up with sofosbuvir. At one time, Achillion Pharmaceuticals' (NASDAQ: ACHN ) pipeline looked incredibly promising and was being led by the non-nucleotide-based inhibitor sovaprevir. With Bristol-Myers Squibb's BMS-986094 shelved after causing the death of a patient in a midstage study, taking Idenix Pharmaceuticals' then-leading hep-C drug candidate with it, Achillion's sovaprevir was expected to be another contender. However, in a recent early stage drug-to-drug interaction study with atazanavir researchers discovered elevated ALT liver enzymes. This led to an ongoing FDA clinical hold on sovaprevir from further studies.

In other words, outside of AbbVie, Gilead has pulled away from many of its peers over the past year.

What should you doWith the briefing document release less than a day away, the thing to remember is not to overreact to the FDA panel's findings. That doesn't mean your fellow shareholders aren't going to overreact, but your long-term thesis on Gilead is likely to be unaltered if the panel points out a few cautionary notes or if it gives sofosbuvir a practical clean bill of health. We will certainly have a lot more to go on by the end of the week (remember that the actual panel meeting is Friday), and will be able to get a more thorough review of the FDA's findings by then.

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Since 1995, the treatment of hepatitis C virus (HCV) infection is based on the combination of twice daily weight-based dosing of ribavirin (RBV) and a weekly subcutaneous injection of pegylated interferon alfa (PR), which achieved a sustained virologic response (SVR) in ∼45% of patients with HCV genotype 1, 65% with HCV genotype 4, 70% with HCV genotype 3, and 80% with HCV genotype 2 infection.1, 2 Although it has been well understood that RBV improves the SVR rate by significantly reducing the occurrence of relapse or virologic breakthrough, the mechanism of action has remained poorly understood, but likely includes immunoregulatory effects. Unfortunately, this clinical benefit has come with a price: RBV increases the incidence of adverse events,1, 2 including clinical symptoms (eg, pruritus, cutaneous rash, neurocognitive troubles) or biochemical perturbations (primarily anemia). RBV -associated anemia is a result of intrinsic hemolysis, suggested to be a result of the accumulation of RBV metabolites within erythrocytes, and enhanced by interferon-associated bone marrow suppression inducing a reduction in anemia-induced reticulocytosis.3

RBV was first approved at a dosing of 11 mg/kg per day, but it was soon appreciated that higher doses were more effective, with the recommended dose increased to 13–15 mg/kg per day. Specifically, retrospective analyses first indicated the dose-effect of RBV irrespective of the genotype, and subsequent data indicated the negative impact of decreased RBV dosing on SVR rates.4, 5 The IDEAL study in naïve genotype 1-infected patients, which compared a 48-week course of 2 different doses of interferon alpha 2b (1 and 1.5 mg/kg per week) versus interferon alpha 2a did not demonstrate any significant difference in the SVR rates across the 3 arms,6 but for the first time showed a positive impact of anemia on the SVR rate.7 In addition, the IDEAL study helped to establish the association between genetic polymorphisms in the inosine triphosphate pyrophosphatase activity (ITPA) gene and RBV-associated anemia in chronic hepatitis C treated patients. These data established the “dogma” that optimization of HCV therapy had to include (1) weight-based dosing of RBV, (2) monitoring of ribavirinemia in suboptimal virologic situation for RBV dose adjustment to reach (yet undefined) thresholds of efficacious RBV exposure, and (3) use of erythropoietin (EPO), instead of RBV dose reduction (RDR), to manage anemia while maintaining the required antiviral potency of the PR combination.8, 9 Thus, physicians were managing anemia associated with antiviral therapies on the scientifically verified basis that maintaining high-dose RBV therapy despite anemia, to not affect negatively the SVR rate,8, 9

A better understanding of the HCV lifecycle has recently resulted in the development of several potential direct-acting antiviral drugs targeting viral proteins (NS3/4A protease inhibitors, NS5B nucleos(t)idic and non nucleos(t)idic polymerase inhibitors, NS5A inhibitors).10 Their combination with or without interferon and/or RBV has established a new era in the management of chronic HCV infections. The first step for this therapeutic revolution was the recent approval in 2011 of the first-generation HCV NS3/4A protease inhibitors boceprevir and telaprevir. Their use for genotype 1–infected patients in triple combinations with PR improved the SVR rates from 45% to nearly 75% in genotype 1–infected, treatment-naïve patients,11, 12 as well as those who previously failed conventional PR treatment.13, 14 Although a major breakthrough, both agents carry a high pill burden: Telaprevir and boceprevir are dosed 2–3 times daily, with 6 and 12 pills per day, respectively (in addition to the 4–7 RBV pills).11, 12, 13, 14 Protease inhibitors are metabolized by CYP3A4- and -3A5, thus requiring consideration of potential drug–drug interactions in patients receiving other treatments.15 They result in significantly more side effects,16 which in addition to those seen for PR, may also include severe cutaneous adverse reactions (telaprevir), anal discomfort (telaprevir), and exacerbated anemia (telaprevir and boceprevir). In the recent studies, rare cirrhosis decompensations and deaths have been reported, mainly related to bacterial infections in Child A cirrhotic patients with albumin levels <35 g/L and platelets count <100,000/mL.17

Indeed, boceprevir or telaprevir triple therapy increases the risk of anemia by ∼20% compared with PR alone: The prevalence of anemia, defined as a hemoglobin of <10 g/dL, is ∼50% with boceprevir and 40% with telaprevir; however, treatment discontinuation owing to anemia is rare.11, 12, 13, 14 During pivotal Phase III trials, boceprevir studies permitted use of EPO, and ∼43% of patients received at least one dose in the course of their HCV therapy.12, 13 By contrast, the telaprevir studies did not permit use of EPO.11, 14 Notably, retrospective analyses of these Phase III studies suggested that reducing the dose of RBV did not alter the SVR rate in treatment-naïve patients,18 in contrast with what has been reported for patients treated with PR therapy.7 In all studies, the use of EPO did not have a positive effect on SVR. However, in the telaprevir study, the very early dose reduction of RBV was associated with a slight decrease in SVR rate.

Poordad et al19 conducted the first prospective randomized trial to determine the impact of RDR (n = 249) versus EPO administration (n = 251) on SVR, for the first-line management of boceprevir-related anemia in genotype-1–naive patients. When hemoglobin level fell to <10 g/dL at any time during treatment, patients were randomized to RDR (200–400 mg as a first step, then a 200-mg step down in RBV dose, to the minimal dosage of 600 mg/d) versus EPO administration at an initial dose of 40,000 IU/wk). A secondary intervention was planned when primary intervention failed: EPO for the RDR arm, RDR for the EPO arm, and blood transfusions. The SVR rates were similar between the 2 groups (71.5% and 70.9%, respectively), regardless of the timing of the first intervention (including the leading phase) or the magnitude of RDR. Moreover, this result was not modified when considering the subgroup of patients that had detectable HCV-RNA at time of randomization. Additionally, only 18% of patients in the RDR arm required EPO, whereas 37% of patients in the EPO arm needed RDR: This second therapeutic intervention did not impact the SVR rate (76% compared with 68% in patients receiving only primary anemia management; P = .146). In the RDR arm, there was a nonsignificant trend (perhaps owing to the limited number of patients) suggestive of higher SVR rates in patients who received secondary interventions: 82 versus 69% (P = .078). Finally, among patients with RDR, SVR rates were lower in those who received lower percentages of the total RBV dose (P = .007), although they received >80% of the assigned treatment duration. It is noteworthy that results were similar in patients with extensive fibrosis or cirrhosis than in those with moderate fibrosis, suggesting that anemia in previously untreated, well-compensated cirrhotic patients can be managed in a manner similar to noncirrhotic patients. Based on their findings, the authors concluded that RDR can be the primary approach for managing anemia in boceprevir triple therapy regimens.

This carefully executed study should help to establish a new standard for the routine management of patients treated by triple therapy: RDR should be the first therapeutic intervention, thereby limiting the potential side effects of blood transfusions and the costly use of EPO (around €917 or $1200 monthly) or its intrinsic risks17: Thromboembolic adverse events were 10-fold more frequent in EPO treated patients (3.1%) compared with patients without EPO (0.3%; P = .003), a risk that has to be balanced in the decision of anemia management.

The helpful therapeutic algorithm of anemia management that the authors propose should be tempered in “difficult-to-treat” patients, for example, cirrhotic or HIV co-infected patients, who are more prone to develop anemia and may have lower SVR rates. Indeed, <10% of randomized patients had cirrhosis and a slight decrease in SVR rate has been previously reported in patients with severe fibrosis who had been managed using RDR strategies. Thus, taking into account the results of phase III and post-approval studies, French guidelines for the management of anemia in telaprevir- and boceprevir-treated patients have recommended the following practices20: In noncirrhotic patients, RDR should be the first-line management of anemia, even when HCV-RNA is still detectable (ie, the dose of RBV can be gradually reduced by 200-mg steps to the minimal dosage of 600 mg/d); additional use of EPO must be discussed on a case-by-case basis, according to clinical symptoms, tolerance of anemia, and comorbidities, and failure of RDR to ameliorate anemia. In cirrhotic patients with detectable HCV-RNA, the RBV dose should be maintained, with management focused on use of EPO until HCV-RNA becomes undetectable. The Poordad's study suggests that we have to reconsider this last proposal in cirrhotic patients, first because, even if a secondary therapeutic intervention (RDR then EPO) should be more frequently expected, SVR seems to not be impacted by RDR, and second because we have to keep in mind safety issues, including thromboembolic adverse events.

With this recent change in management of chronic HCV (which we support as first-line management of anemia), we also become hopeful for further simplification of treatment guidelines. We know that second-wave direct-acting antiviral drugs have less hematologic toxicity and that the expected availability of interferon- and RBV-free regimens combining oral direct-acting antiviral drugs will rapidly make these recommendations obsolete. Nonetheless, vigilance regarding treatment-induced anemia is important, and may remain as part of the management plan for resource limited countries that continue to use PR as the therapeutic backbone for chronic HCV treatment.

Acknowledgments

S. Pol thanks Dr Matthew Albert for his help in the preparation of the manuscript.

The Veterans Health Administration (VHA) is the largest single provider of care for hepatitis C virus (HCV) infection in the United States. We analyzed the cost effectiveness of treatment with the HCV protease inhibitors boceprevir and telaprevir in a defined managed care population of 102,851 patients with untreated chronic genotype 1 infection.

Methods

We used a decision-analytic Markov model to examine 4 strategies: standard dual-therapy with pegylated interferon-alfa and ribavirin (PR), the combination of boceprevir and PR triple therapy, the combination of telaprevir and PR, or no antiviral treatment. A sensitivity analysis was performed. Sources of data included published rates of disease progression, the census bureau, and VHA pharmacy and hospitalization cost databases.

Results

The estimated costs for treating each patient were $8000 for PR, $31,300 for boceprevir and PR, and $41,700 for telaprevir and PR. Assuming VHA treatment rates of 22% and optimal rates of sustained virologic response, PR, boceprevir and PR, and telaprevir and PR would reduce relative liver-related deaths by 5.2%, 10.9%, and 11.5%, respectively. Increasing treatment rates to 50% would reduce liver-related deaths by 12%, 24.7%, and 26.1%, respectively. The incremental cost-effectiveness ratios were $29,184/quality-adjusted life-years for boceprevir and PR and $44,247/quality-adjusted life-years for telaprevir and PR vs only PR. With the current 22% treatment rate, total system-wide costs to adopt boceprevir and PR or telaprevir and PR would range from $708 to $943 million.

Conclusions

Despite substantial up-front costs of treating HCV-infected patients in the VHA with PR, or telaprevir and PR, each regimen improves quality of life and extends life expectancy by reducing liver-related morbidity and mortality, and should be cost effective. Further efforts to expand access to direct-acting antiviral therapy are warranted.

Conflicts of interest This author discloses the following: Samuel Ho has received research and grant support from Genetech, Inc, Vital Therapies, Inc, and Aspire Bariatrics, Inc; and has received expert panel fees from Roche Pharmaceuticals, Inc. The remaining authors disclose no conflicts.

Funding Supported by the Department of Veterans Affairs Health Services Research and Development Quality Enhancement Research Initiative (RRP 10-228).

The ultimate goal of hepatitis B treatment is to prevent progression to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). This goal can be achieved with sustained suppression of hepatitis B virus (HBV) replication and hepatic inflammation. Current treatment guidelines for hepatitis B recommend antiviral therapy for patients with active or advanced liver disease and high serum HBV DNA levels.1, 2, 3, 4 For patients who do not have cirrhosis, these guidelines recommend that the decision to start treatment or to monitor should be based not only on the stage of liver fibrosis but also on the activity of liver disease and the predicted risk of cirrhosis and HCC. Unlike hepatitis C (HCV) where the vast majority of HCC cases occur in patients with cirrhosis, 3%–47% of HBV-related HCC occurs in the absence of cirrhosis.5, 6, 7 One major difference between HBV and HCV is that HBV is a DNA virus, and HBV DNA can be integrated into the host genome and may have direct oncogenic effect through activation of oncogenic pathways or down-regulation of tumor suppressor pathways.8, 9 Furthermore, ample evidence mainly generated from the population-based Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus study shows that high levels of serum HBV DNA are associated with increased risk of cirrhosis, HCC, and liver-related mortality.10

Professional society guidelines agree that treatment should be initiated in non-cirrhotic patients with serum HBV DNA >20,000 IU/mL and alanine aminotransferase (ALT) levels higher than 2 times upper limit of normal (ULN) or histologic evidence of moderate-to-severe inflammation or fibrosis. The cutoff values of ALT, HBV DNA, and the need for liver biopsy in determining treatment indications vary slightly among the guidelines.11 Because HBV DNA levels are generally lower in hepatitis B e antigen (HBeAg)–negative patients, cutoff values for initiating treatment in HBeAg-negative patients are lower than in HBeAg-positive patients. Recognizing that liver biopsy is not performed on all patients with chronic hepatitis B, the guidelines of the American Association for the Study of Liver Diseases (AASLD) and the Asian Pacific Association for the Study of the Liver (APASL) primarily rely on ALT levels to guide treatment decisions.1, 2

For HBeAg-negative patients with HBV DNA 2000–20,000 IU/mL, the AASLD and APASL guidelines recommend treatment for patients with ALT levels higher than 2 times ULN and liver biopsy to guide treatment decisions for patients with ALT level 1–2 times ULN, particularly if they are older than the age of 40. United States Panel Algorithm (USPA) recommends liver biopsy in patients older than age 35–40 who have serum HBV DNA ≥2000 IU/mL and normal ALT levels.4 USPA and AASLD suggest using the updated ULN for ALT, 30 U/L for men and 19 U/L for women, whereas the European Association for the Study of the Liver (EASL) and APASL suggest the traditional definition of ULN for ALT (40 U/L). The EASL guidelines place more emphasis on liver histology; they recommend treatment of patients with ALT above ULN if liver biopsy shows at least a metavir activity grade of A2 (range, 0–3) or a metavir fibrosis score of F2 (range, 0–4).3 The 2012 EASL guidelines indicate that validated noninvasive assessment may replace liver biopsy to stage liver fibrosis. APASL, USPA, and EASL guidelines recommend an HBV DNA threshold of 2000 IU/mL for HBeAg-negative patients, whereas AASLD recommends a cutoff of 20,000 IU/mL. The recommendations of AASLD, APASL, EASL, and USPA are summarized in Figure 1. All guidelines specifically addressed that lower ALT and HBV DNA thresholds should be used in older patients and patients with a family history of HCC. Moreover, because of the fluctuating nature of chronic HBV infection, serial monitoring of HBV DNA is more important than a single measurement in determining the prognosis and the need for therapy.

In this issue of the journal, Sanai et al12 assessed the accuracy of the guideline-defined thresholds for initiating treatment in HBeAg-negative patients in identifying those with metavir fibrosis stage ≥F2 (range, 0–4). The authors retrospectively reviewed the records of 366 consecutive HBeAg-negative patients who underwent liver biopsy at 4 centers in Saudi Arabia between January 2006 and January 2012. Patients coinfected with HCV, human immunodeficiency virus, or hepatitis D virus, those with other causes of liver disease, decompensated cirrhosis, and patients on immunosuppressive or antiviral therapy were excluded. A criterion for inclusion was the availability of multiple ALT and HBV DNA results before the biopsy. The last 3 serum ALT and HBV DNA levels before the liver biopsy were used to determine whether each patient did or did not meet guideline threshold for initiating antiviral therapy. Patients needed to have 3 normal ALT values or 3 HBV DNA <20,000 IU/mL to be considered normal or below threshold and 2 elevated ALT values or 2 HBV DNA ≥20,000 IU/mL to be considered above threshold. Different assays and different ULNs were used to measure ALT at the 4 study sites; therefore, ALT levels as a ratio of the ULN for each laboratory were used in the analysis. To determine whether the ALT value of any given patient is above or below the updated ULN proposed by Prati et al,13 the authors assumed that the proposed ULNs of 30 U/L for men and 19 U/L for women are equivalent to 0.75-fold and 0.50-fold, respectively, the ULN assigned by any laboratory because the laboratory-assigned ULN in their study was 40 U/L. All the biopsies were staged for fibrosis according to the metavir system by 2 pathologists who were blinded to all clinical information.

The authors found that 53 (14.5%), 173 (47.3%), 171 (46.7%), and 87 (23.8%) patients met the definite treatment criteria of the AASLD, USPA, EASL, and APASL guidelines, respectively. Among 113 patients (30.9%) who had significant fibrosis defined as metavir fibrosis score ≥F2, 79 (69.9%) met at least one guideline definite treatment criterion. The sensitivity of AASLD, USPA, EASL, and APASL definite treatment criteria in predicting metavir ≥F2 was 58.5%, 45.7%, 45.6%, and 56.3%, respectively, and the specificity was 73.8%, 82.4%, 82.1%, and 77.1%, respectively. The authors concluded that in general, the threshold HBV DNA and ALT levels for definite treatment were relatively good at correctly identifying individuals without significant fibrosis, but these threshold values had dismally low positive predictive values and would lead to treatment initiation in a high proportion of individuals without significant disease.

The study by Sanai et al12 has several strengths. The study included a reasonably large number of patients who underwent liver biopsy, and all the patients had more than one ALT and HBV DNA levels before liver biopsy. In addition, all the biopsies were scored by 2 central pathologists who were blinded to clinical data.

However, there are major problems with this study. First and foremost, the study was misguided. The authors mistakenly assumed that ALT and HBV DNA were used as markers of fibrosis to guide treatment decision. This is far from the truth. Although there is no doubt that hepatitis B patients with advanced fibrosis should receive antiviral treatment, treatment is also recommended for patients with high levels of HBV DNA and active liver disease (on the basis of serum ALT or hepatic inflammation). The importance of persistently high viral load and hepatic inflammation on the outcomes of patients with chronic HBV infection is the basis for using HBV DNA and ALT levels as criteria for initiating treatment in the AASLD, USPA, EASL, and APASL guidelines. As discussed earlier, 18%–47% of HBV-related HCC occurs in the absence of cirrhosis, and high levels of HBV DNA have been shown to be a strong predictor of cirrhosis, HCC, and liver-related mortality; therefore, indications for treatment of hepatitis B should not be based solely on liver fibrosis.5, 6, 10

There are other limitations in this study. The authors used 2 or 3 most recent ALT and HBV DNA levels before the biopsy to determine whether definite treatment criteria are met. The interval between the most recent ALT and HBV DNA levels and the liver biopsy was not specified; however, the authors stated that the median (interquartile range) periods of ALT and HBV DNA observations before the biopsy were 21 (8–46) months and 9 (5–18) months, respectively, suggesting that the interval may be quite long in some patients. A long interval between HBV DNA and ALT levels and the biopsy and fluctuations in HBV DNA and ALT levels during that period would lower the accuracy of these markers in predicting liver fibrosis. Indeed, the authors indicated that 22.7% and 15% of patients had HBV DNA levels fluctuating above or below 2000 and 20,000 IU/mL. It is possible that a similar proportion of patients had ALT levels fluctuating above or below the thresholds for initiating treatment. The authors did not indicate how patients with fluctuating HBV DNA or ALT levels were categorized.

An interesting aspect of this study was the adjustment of ALT values reported to the updated ULN proposed by Prati et al.13 The adjustment method assumes that the absolute ALT values obtained by different assays are equivalent, and a ULN of 40 in one laboratory is the same as a ULN of 60 in another laboratory. Neither assumption has been validated.

Determination of fibrosis stage is an important step in the management of hepatitis B; however, fibrosis is not the only indication for hepatitis B treatment. Age of the patient, HBV replication status, activity of liver disease, and family history of HCC should also be considered in deciding whom to treat and when to initiate treatment. Because currently available treatment for hepatitis B does not eradicate the virus, necessitating long durations and in many instances lifelong treatment, we agree with Sanai et al12 that criteria for initiating hepatitis B treatment in guidelines must be carefully weighed to avoid unnecessary treatment.

Conflicts of interest This author discloses the following: Anna S. Lok received research grants from Bristol-Myers Squibb, Gilead, and Merck and served as advisor for Gilead, GlaxoSmithKline, and Merck. The remaining author discloses no conflicts.

Funding Suna Yapali received support from Turkish Association for The Study of the Liver. Suna Yapali and Anna S. Lok received support from the Tuktawa Foundation through the Alice Lohrman Andrews Professorship.

Because of widespread skepticism regarding the safety of Western medication, there is great interest in studying alternative treatments that are considered natural and safe from toxicities.1 Many foods and diets are believed to promote health and longevity.2 Coffee is a beverage with a distinct taste and aroma that commonly is consumed throughout the world and is being assessed for its potential health benefits.3 For instance, a decreased risk of type 2 diabetes, heart disease, and stroke has been described in regular coffee drinkers.4, 5, 6 In a recent analysis of the National Institutes of Health–AARP Diet and Health Study data published by Freedman et al,7 the investigators described a dose-dependent inverse association between coffee consumption and total mortality.

Chronic liver disease is a major health burden in the United States.8 Treatment for many causes of liver disease is limited by significant adverse effects or a lack of efficacious medications.9 There has been increasing interest in the hepatoprotective properties of coffee consumption.10 Coffee consumption has been observed to have an inverse association with serum levels of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyltransferase.11, 12 In a large cross-sectional US study, intake of regular ground coffee and caffeine intake was associated with a decreased risk of progression of chronic liver disease.13 Those who drank more than 2 cups of coffee daily over a median follow-up period of 19 years had less than half the rate of chronic liver disease than those who drank less than 1 cup daily. A decreased rate of hepatic fibrosis progression was described in patients who consumed more than 2 cups of caffeinated coffee by Modi et al (odds ratio, 0.33; 95% confidence interval [CI], 0.14–0.8; P = .015).14 Not only has coffee been associated with a decrease in a number of liver diseases, but its consumption also may decrease liver-related mortality.7

In this issue of Clinical Gastroenterology and Hepatology, Bravi et al15 performed a meta-analysis examining the relation between coffee consumption and the risk of developing hepatocellular carcinoma (HCC). This study was performed as an update to their previous meta-analysis that was published in 2007.16 The current meta-analysis combined the results from 16 studies, 8 of which were case-cohort studies and the other 8 were case-control studies. The total number of cases combined from the 16 studies was 3153 patients with HCC. The investigators found that the summary relative risk (RR) of developing HCC with coffee consumption was 0.60 (95% CI, 0.50–0.71) overall. The data were stratified further according to the amount of coffee consumption. The summary RR was 0.72 (95% CI, 0.61–0.84) based on 14 studies comparing low coffee consumption vs no coffee consumption. The summary RR was 0.44 (95% CI, 0.39–0.50) overall high coffee consumption vs no consumption. From the data, the investigators extrapolated that the RR estimate for each extra cup of coffee consumed daily was 0.80 (95% CI, 0.77–0.84). The investigators showed an inverse relation between coffee consumption and HCC risk, even when stratifying for sex, alcohol use, or cause of underlying liver disease. The HCC-specific action is highlighted further by the negative association reported by another study of pancreatic cancer in this issue.17

Although the results are promising that coffee consumption has an inverse relation to the development of HCC, applying these results to daily practice still may yet be elusive. Additional work is needed to identify which specific component of coffee is the contributing factor in reducing liver disease and related mortality. Although the main compounds in coffee implicated to have protective roles in the liver are caffeine and chlorogenic acid, there are more than 1000 compounds that could be responsible for its beneficial effects.18 Caffeine is thought to play a role in protecting against hepatic fibrosis. One mechanism, proposed by Gressner,19 is that caffeine plays a role in the degradation of Smad2 and Smad3 proteins, which are mediator proteins of transforming growth factor β, a profibrogenic signaling pathway. Caffeine also is thought to affect the hepatic detoxification process by activating uridine 5′-diphospho-glucuronosyltransferase.20 Coffee-specific diterpenes, kahweol and cafestol, also may confer hepatoprotective effects via activation of the cis-acting antioxidant-responsive element sequence21 (Table 1).

Other commonly consumed beverages also have been studied for their effect on chronic liver disease. In a study examining the relationship between coffee and tea consumption with the incidence of death or hospitalization from chronic liver disease, regular coffee consumption was associated with less than half the rate of liver disease than in patients who drank no coffee, or in patients who drank decaffeinated coffee. Decaffeinated coffee did not have the same hepatoprotective effects when compared with regular coffee, with a multivariate-adjusted hazard ratio of 1.3 (95% CI, 0.58–3.0) vs 0.5 (95% CI, 0.27–1.0).13 When studying the effect on HCC, there was a decreased risk of HCC with increasing coffee consumption, but no significant associations were seen with decaffeinated coffee or tea.22, 23

Coffee consumption is not without potential conflicts. Coffee ingestion can have immediate effects, such as feeling jittery, and also has systemic cardiovascular effects, such as increasing blood pressure and heart rate.24 Daily consumption of caffeinated beverages also can lead to physical dependence. Discontinuation of caffeine intake can lead to withdrawal symptoms such as headache, fatigue, difficulty with concentration and memory, and mood disturbances.25 This potentially can be significantly debilitating because patients with chronic liver disease already often suffer from fatigue, depression, and memory changes.26

There are numerous limitations when interpreting the studies regarding the health benefits of coffee. The lack of standardization of coffee preparations and serving sizes among various studies leads to ambiguity regarding how much coffee intake is necessary for these effects to be seen. The duration of coffee consumption to yield a protective effect is also unknown. Although the aforementioned studies provide compelling evidence to suggest that coffee is useful as an adjunct treatment of liver disease in reducing the risk of HCC, further trials would need to be performed to provide evidence for causation, to eliminate confounding variables, and to determine an acceptable standardized dose and preparation of coffee needed to see hepatoprotective effects. Nevertheless, coffee is relatively inexpensive and readily available. The data from Bravi et al16 indeed illustrate that coffee consumption is associated with a decreased risk of HCC in an elegant meta-analysis of the literature. Patients at risk of HCC should be encouraged to continue consuming coffee if they already are doing so. Coffee-naive patients should consider the risks and benefits before recommendations are made to start drinking coffee.

Category:

Public Company Information:

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Merck (NYSE:MRK), known as MSD outside the United States and Canada, announced today that the U.S. Food and Drug Administration (FDA) has granted MK-5172/MK-8742 Breakthrough Therapy designation for treatment of chronic hepatitis C virus infection. MK-5172/MK-8742 is an all-oral combination regimen consisting of MK-5172, an investigational HCV NS3/4A protease inhibitor, and MK-8742, an investigational HCV NS5A replication complex inhibitor. Interim data from an ongoing Phase IIB clinical trial evaluating MK-5172/MK-8742 in genotype 1 infected patients (C-WORTHY Study) is scheduled to be presented at the 64th American Association for the Study of Liver Disease Annual Meeting, Washington D.C., Nov. 1-5.

“The designation of MK-5172/MK-8742 as a Breakthrough Therapy for chronic hepatitis C is an important milestone for Merck,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “There remains significant unmet medical need in hepatitis C, and we are looking forward to working with the FDA to advance this program as quickly as we can to bring this investigational combination to HCV specialists and their patients.”

According to the FDA, the designation of an investigational drug as a Breakthrough Therapy is intended to expedite the development and review of a candidate that is planned for use, alone or in combination, to treat a serious or life-threatening disease or condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.

Chronic hepatitis C is a priority focus of research and development at Merck. MK-5172 and MK-8742 are being investigated in a broad clinical program that includes studies in patients with multiple HCV genotypes who are treatment-naïve, treatment failures as well as other important HCV subpopulations such as patients with cirrhosis and those co-infected with HIV. For more information please see www.clinicaltrials.gov.

About Merck

Today's Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. Through our prescription medicines, vaccines, biologic therapies and consumer care and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2012 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

BRUSSELS — Joop Arends, MD, PhD, an infectious disease specialist at the University Medical Center Utrecht in the Netherlands, discusses his presentation at EACS 2013 on the effect of triple therapy (telaprevir or boceprevir with pegylated interferon and ribavirin) on HIV/HCV coinfected patients with cirrhosis. In the study, triple therapy using either telaprevir or boceprevir was effective at 24 weeks, but severe anemia was common in the cohort.

Johnson & Johnson ($JNJ) and its partner Medivir took another big step toward the booming hepatitis C market today, earning a positive internal review at the FDA for simeprevir. But analysts concluded that a substantial subpopulation of patients infected with a particular polymorphism variant won't likely benefit from the NS3/4A protease inhibitor, leaving that field open to some big rivals contending for near-term approvals.

About 58% of the hep C patients in the genotype 1a population had a Q80K polymorphism, and they fared about the same as patients in the control arm in the late-stage study. Regulators are recommending that any approval for the therapy should be attached to a provision weeding out that large group of patients. But the application looks to be headed to clear sailing in a panel review scheduled for Thursday, a day ahead of Gilead's ($GILD) big show for sofosbuvir.

"The results of the clinical development program indicate that SMV + PR is a well-tolerated and effective therapeutic alternative for HCV-infected patients," notes the FDA. "Simeprevir 150 mg once daily for 12 weeks + PR is associated with high SVR rates, a good tolerability and drug-drug interaction profile, a simple 24-week regimen in all treatment-naïve and prior relapser patients including cirrhotics, and a convenient single capsule once daily dosing that could reduce treatment burden on patients." The data back up the use of simeprevir for partial and null responders.

While Gilead has been stealing the show with stellar data on its hep C drug sofosbuvir, J&J and Medivir have been making steady progress on their own. And while sofosbuvir is given the starring role in the development of new cocktail therapies that can control the virus without the use of interferon injections, simeprevir is likely to find a place for itself in this market as well. But its market potential will rely heavily on how often it can be included in cocktail remedies.

Peak sales estimates for this drug vary widely, which isn't uncommon. Bernstein's Tim Anderson expects revenue to top out at $400 million in 2016 before it begins a downward spiral. In addition to Gilead, which is developing its own in-house cocktail for various hep C patient groups, AbbVie ($ABBV) has been hustling along with its competing therapy. Bristol-Myers Squibb ($BMY) and others are also active in the field.

An experimental hepatitis C drug from Johnson & Johnson appears to be slightly more effective at eliminating the virus than currently available treatments, though federal safety reviewers say it also causes rash and sunburn in some patients.

The Food and Drug Administration posted its review of simeprevir online ahead of a public meeting Thursday where experts will vote on whether to recommend the drug's approval.

More than 3 million people in the United States have hepatitis C, a blood-borne disease linked to 15,000 deaths a year. The disease slowly eats away at the liver over 20 to 30 years and most people don't even realize they have the virus until after liver damage occurs.

Drugmakers see hepatitis treatments as potentially lucrative because the disease is expected to grow into a major public health problem as the U.S. baby boom generation ages.

For most of the last 20 years, the standard treatment for hepatitis C involved a grueling one-year regimen of pills and injections that caused flu-like symptoms and cured less than half of patients. Then in 2011, the FDA approved two new drugs from Merck and Vertex Pharmaceuticals that raised the cure rate to about 65 and 75 percent, respectively, when combined with the older treatments.

J&J's new drug appears to raise the level of effectiveness again: simeprevir cured 80 percent of patients who had not previously been treated for the disease, according to the FDA. The New Brunswick, N.J., company is seeking approval to combine the drug with the standard treatment regimen for patients with the most common form of the virus.

But the agency's review is not all positive. FDA scientists note that 25 percent of patients taking the drug developed a rash during the first 12 weeks of treatment. About 5 percent of patients also developed sunburn as a side effect of the drug.

On Thursday the FDA will ask a panel of outside experts whether the drug should carry warnings about rashes and sunburn on its label. The agency also wants to know whether "sun-protection measures should be recommended for all patients."

The FDA is not required to follow the advice of its panelists, though it often does.

The same panel of experts will review another proposed hepatitis C drug from Gilead Sciences Inc. on Friday. Some analysts expect that drug, known as sofosbuvir, to become the leading drug for the disease, based on research showing it cured 90 percent of patients in 12 weeks.

Johnson & Johnson (JNJ)’s and Medivir AB (MVIRB)’s experimental hepatitis C treatment is safe and effective, U.S. regulators said, providing a boost to the companies as they try to reach a highly competitive market for new treatments.

The drug known as simeprevir helps cure patients of the infectious disease that can lead to a liver transplant, Food and Drug Administration staff said in a review today ahead of an Oct. 24 meeting of agency advisers to discuss the medicine. The FDA is scheduled to decide whether to approve simeprevir for sale by Nov. 27.

The FDA report recommended potential users of the drug should be screened for a mutation called Q80K polymorphism that is linked to resistance.

J&J, based in New Brunswick, New Jersey, and Medivir, based in Huddinge, Sweden, are seeking approval for their once daily pill to treat chronic hepatitis C patients with the genotype 1 infection, the most common form of the condition, who have liver disease and haven’t been treated before or who have failed interferons.

Disclaimer: The statements contained in this document(s) are those of the product's sponsor, not FDA, and FDA does not necessarily agree with the sponsor's statements. FDA has not made a final determination about the safety or effectiveness of the product described in this document.

Stockholm, Sweden — Medivir AB (OMX: MVIR) In March 2013,Medivir’s partner Janssen Pharmaceuticals, Inc. (Janssen) filed a new drug application (NDA) with the U.S. Food and Drug Administration (FDA) seeking approval for simeprevir for a triple combination treatment of simeprevir combined with pegylated interferon and ribavirin in patients infected with chronic genotype 1 hepatitis C. In May 2013, the FDA granted Priority Review to the new drug application for simeprevir.

Next step in the regulatory process is scheduled to be on 24 October 2013 when the FDA’s Antiviral Drugs Advisory Committee is scheduled to meet to review the application for simeprevir.

The Committee is scheduled to meet from 8am to 5pm Eastern Standard Time (EST), ending with a voting session. The outcome is typically announced by the FDA after the meeting. Medivir will issue a press release about FDA’s announcement. The FDA is then expected to make its final decision by end of November 2013. That decision will also be announced through a press release.

A Briefing Book, which contains information about simeprevir and its clinical studies, is available on the FDA website.

There is no planned trading halt in the Medivir share on 24 October 2013.

About MedivirMedivir is an emerging research-based pharmaceutical company focused on infectious diseases. Medivir has world class expertise in polymerase and protease drug targets and drug development which has resulted in a strong infectious disease R&D portfolio. The Company’s key pipeline asset is simeprevir, a novel protease inhibitor for the treatment of hepatitis C that is being developed in collaboration with Janssen R&D Ireland. The company is also working with research and development in other areas, such as bone disorders and neuropathic pain.

Medivir has also a broad product portfolio with prescription pharmaceuticals in the Nordics.

For more information about Medivir AB, please visit the Company’s website: www.medivir.com

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